The aryl hydrocarbon receptor instructs the immunomodulatory profile of a subset of Clec4a4+ eosinophils unique to the small intestine

Significance Eosinophils contribute to type 2 immunity against helminths and allergens. The small intestine harbors eosinophils with incompletely understood pathophysiological roles. Here, we show that intestinal eosinophils include two subsets. One expresses the inhibitory receptor Clec4a4 and the inhibitory ligand PD-L1 and is unique to the small intestine; the other manifests a proinflammatory phenotype. Both subsets are blood derived. Remarkably, Clec4a4+ eosinophils were instructed by the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that imprints many gut immune cells. Selective AHR deletion in eosinophils depleted Clec4a4+ eosinophils, augmented innate lymphocytes producing type 2 cytokines, and enhanced helminth clearance. We conclude that Clec4a4+ eosinophils have immunomodulatory functions, which could be harnessed for the therapy of food allergies and eosinophilic gastrointestinal disorders.

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